WO2002096419A1 - Composition pharmaceutique comprenant un compose tricyclique utile pour prevenir ou traiter les dermatoses - Google Patents

Composition pharmaceutique comprenant un compose tricyclique utile pour prevenir ou traiter les dermatoses Download PDF

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Publication number
WO2002096419A1
WO2002096419A1 PCT/JP2002/005030 JP0205030W WO02096419A1 WO 2002096419 A1 WO2002096419 A1 WO 2002096419A1 JP 0205030 W JP0205030 W JP 0205030W WO 02096419 A1 WO02096419 A1 WO 02096419A1
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Prior art keywords
group
hydrogen atom
hydroxy
pharmaceutical composition
alkyl
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PCT/JP2002/005030
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English (en)
Inventor
Satoshi Ueda
Toshiro Sakai
Erika Yoshida
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to EP02730703A priority Critical patent/EP1392297A1/fr
Priority to CA002448248A priority patent/CA2448248A1/fr
Priority to US10/478,635 priority patent/US20040220204A1/en
Priority to JP2002592929A priority patent/JP2005500269A/ja
Priority to BR0210251-0A priority patent/BR0210251A/pt
Priority to IL15890002A priority patent/IL158900A0/xx
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to MXPA03010760A priority patent/MXPA03010760A/es
Priority to PL02367634A priority patent/PL367634A1/xx
Priority to HU0400020A priority patent/HUP0400020A2/hu
Priority to KR10-2003-7015071A priority patent/KR20040002980A/ko
Publication of WO2002096419A1 publication Critical patent/WO2002096419A1/fr
Priority to NO20035230A priority patent/NO20035230D0/no

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    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Definitions

  • This invention relates to a pharmaceutical composition containing tricyclic compound, said composition being stable and having very satisfactory absorption kinetics and/or a low irritation potential.
  • This composition finds application in the therapy and prophylaxis of various diseases of the skin.
  • the tricyclic compound and its pharmaceutically acceptable salt for use in accordance with this invention is known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs . -host diseases , autqimmune diseases , and infectious diseases [EP-A-0184162 , EP-A-0323042 , etc.].
  • FK506 Substance among such tricyclic compound ( I ) which has been shown to be useful for the therapy and prevention of graft rejection in organ transplantation due to its quite excellent immunosuppressive activity.
  • FK506 Substance is effective in arresting inflammatory reactions and that FK506 Substance can be provided in the form of a lotion, a gel or a cream. However, there is no specific disclosure of such dosage forms.
  • EP-A-0474126 discloses an ointment comprising FK506 Substance and its analogs, a dis solution/absorption promoter added in a sufficient amount to dissolve the active compound, and an ointment base.
  • 094/28894 discloses a lotion comprising FK506 Substance and its analogs, a dissolution/absorption promoter, a liquid base, and, optionally, an emulsifier and/or a thickener.
  • W099/55332 discloses a pharmaceutical composition
  • a pharmaceutical composition comprising macrolide compound, a dissolution/absorption promoter and a pharmaceutical base, and optionally a compatibilizing agent and/or a thickener.
  • the inventors of this invention explored in earnest for a pharmaceutical composition suited for the administration of a tricyclic compound, a representative of which is FK506 Substance, and discovered a dosage form having very satisfactory characteristics, namely stability, good percutaneous absorption and/or low skin irritation potential.
  • the present invention specifically relates to a gel preparation comprising the tricyclic compound for external application.
  • a pharmaceutical composition comprising the tricyclic compound (I) or its pharmaceutically acceptable salt; monohydric alcohol fatty acid esters; dibasic acid diesters; lower alkylene carbonates; butylene glycol; diethylene glycol mono (lower) alkyl ethers; and thickeners .
  • R 2 is two adjacent hydrogen atoms, but R 2 may also be an alkyl group or
  • (b) may form another bond formed between the carbon atoms to which they are attached;
  • R 7 is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with R 1 ;
  • R 8 and R 9 are independently a hydrogen atom or a hydroxy group
  • R 10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group ;
  • X is an oxo group, (a hydrogen atom and a hydroxy group) ,
  • R 11 and R 12 are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 are independently a hydrogen atom or an alkyl group
  • R 24 is an optionally substituted ring system which may contain one or more heteroatoms
  • n is an integer of 1 or 2
  • Y, R 10 and R 23 together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula -
  • lower means, unless otherwise indicated, a group having 1 to 6 carbon atoms .
  • alkyl groups and an alkyl moiety of the "alkoxy group” include a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl .
  • alkenyl groups include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl , pentenyl and hexenyl .
  • a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl , pentenyl and hexenyl .
  • aryl groups include phenyl , tolyl, xylyl, cumenyl, mesityl and naphthyl .
  • Preferable protective groups in the "protected hydroxy groups" and the "protected amino" are 1- (lower alkylthio) - (lower) alkyl group such as a lower alkylthiomethyl group (e.g. , methylthiomethyl , ethylthiomethyl, propylthiomethyl , isopropylthiomethyl , butylthiomethyl, isobutylthiomethyl, hexylthiomethyl , etc.), more preferably Ci -C 4 alkylthiomethyl group, most preferably methylthiomethyl group; trisubstituted silyl group such as a tri ( lower ) alkylsilyl (e.g., trimethylsilyl , triethylsilyl , tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl , etc.) or lower alkyl-diarylsilyl (e
  • acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
  • aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl , carboxyhexanoyl , etc.; a cyclo ( lower) alkoxy (lower ) alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl , cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl , menthyloxybutyryl, menthyloxypentanoyl , menthyloxyhe
  • aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl , nitronaphthoyl , etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl , etc.
  • suitable substituents such as nitro, e.g., benzoyl, toluoyl,
  • Examples of the aliphatic acyl groups substituted by an aromatic group include ar (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower ) alkyl , e.g., phenylacetyl , phenylpropionyl , phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl , 2-ethyl-2-trifluoromethyl-2-phenylacetyl , 2-trifluoromethyl-2-propoxy-2-phenylacetyl , etc .
  • ar (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower ) alkyl , e.g., phenylacetyl , phenylpropionyl , phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl
  • acyl groups among the aforesaid acyl groups are C 1 -C 4 alkanoyl group optionally having carboxy, cyclo (C 5 -C 6 ) alkoxy (C ⁇ -C 4 ) alkanoyl group having two (C1-C4) alkyls at the cycloalkyl moiety, ca phorsulfonyl group, carboxy- (C 1 -C 4 ) alkylcarbamoyl group, tri (C ⁇ C 4 ) alkylsilyl (C 3.
  • the most preferable ones are acetyl, carboxypropionyl , menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethy1-2 -methoxy-2-phen lacetyl .
  • Preferable examples of the "5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring" include a pyrrolyl group and a tetrahydrof ryl group.
  • R 24 is an optionally substituted ring system which may contain one or more heteroatoms, Preferable R 24 may be cyclo (C 5 - 7 ) alkyl group optionally having suitable substituents, and the following ones can be exemplified.
  • acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified
  • acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified
  • amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl .
  • a preferred example is a 2-formyl-cyclopentyl group.
  • a heteroaryl which may be substituted by suitable substituents moiety of the "heteroaryloxy which may be substituted by suitable substituents” may be the ones exemplified for R 1 of the compound of the formula of EP-A-532 , 088 , with preference given to 1-hydroxyethylindol -5-yl, the disclosure of which is incorporated herein by reference .
  • ticyclic compounds (I) and its pharmaceutically acceptable salt for use in accordance with this invention are well known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs-host diseases, autoimmune diseases, and infectious diseases [EP-A-0184162 , EP-A-0323042 , EP-A-423714, EP-A-427680, EP-A-465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337, EP-A-626385, WO89/05303, WO93/05058, 096/31514, W091/13889, W091/19495, WO93/04680, O93/5059, etc.], the disclosures of which are incorporated herein by reference.
  • FK506 (general name: tacrolimus) of the following chemical formula, inparticular, is a representative compound.
  • tricyclic compounds (I) are the ones, wherein each of adjacent pairs of R 3 and R 4 or R 5 and R ⁇ independently form another bond formed between the carbon atoms to which they are attached; each of R 8 and R 23 is independently a hydrogen atom;
  • R 9 is a hydroxy group
  • R 10 is a methyl group, an ethyl group, a propyl group or an allyl group
  • X is (a hydrogen atom and a hydrogen atom) or an oxo group
  • Y is an oxo group
  • each of R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 22 is a methyl group
  • R 24 is a 3-R 20 -4-R 21 -cyclohexyl group, in which R 20 is hydroxy, an alkoxy group, an oxo group, or a -OCH 2 OCH 2 CH 2 OCH 3 group, and R 21 is hydroxy, -OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, 1- or 2-tetrazolyl , a -OCH 2 OCH 2 CH 2 OCH 3 group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy , or R 25 R 26 CHCOO-, in which R 25 is optionally protected hydroxy or protected amino, and R 26 is hydrogen or methyl, or R 20 and R 21 together form an oxygen atom in an epoxide ring; and n is an integer of 1 or 2.
  • the most preferable tricyclic compounds (I) is, in addition to FK506, ascomycin derivatives such as halogenated-ascomycin (e.g., 33-epi-chloro-33-desoxyascomycin) , which is disclosed in EP 427,680, example 66a.
  • the tricyclic compounds ( I ) may be in a form of its salt, which includes conventional non-toxic and pharmaceutically acceptable salt such as the salt with inorganic or organic bases, specifically, an alkali metal salt such as sodium salt and potassium salt, an alkali earth metal salt such as calcium salt and magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.
  • tricyclic compound (I) used in the present invention there may be conformers and one or more stereoisomers such as optical and geometrical isomers due to asymmetric carbon atom(s) or double bond(s) , and such conformers and isomers are also included within the scope of tricyclic compound (I) in the present invention.
  • the tricyclic compound(I) can be in the form of a solvate, which is included within the scope of the present invention.
  • the solvate preferably include a hydrate and an ethanolate.
  • Monohydric alcohol fatty acid esters, dibasic acid diesters and lower alkylene carbonates for use in this invention are not particularly restricted provided that they are capable of dissolving tricyclic compound (I) or its pharmaceutically acceptable salt therein and/or promoting its percutaneous absorption.
  • the following examples can be used with advantage.
  • diisopropyl adipate dimethyl adipate, diethyl adipate, diethyl sebacate, diisopropyl sebacate, dipropyl sebacate, diethyl phthalate, diethyl pimelate, etc.
  • diisopropyl adipate, diethyl sebacate or their combination are the most preferable ones.
  • each amount of said monohydric alcohol fatty acid esters, dibasic acid diesters and lower alkylene carbonates in the composition is not particularly restricted but should be large enough to. dissolve the tricyclic compound (I) and/or promote its percutaneous absorption.
  • each amount thereof is preferably 1-30% (w/w), more preferably 2-20% (w/w) , still more preferably 3-15% (w/w) .
  • the total amount of said monohydric alcohol fatty acid esters, dibasic acid diesters and lower alkylene carbonates in the composition is preferably 5-50% (w/w) , more preferably 7-35% (w/w) , still more preferably 9-25% (w/w) .
  • butylene glycol for use in this invention are 1 , 3-butylene glycol , 1, 2-butylene glycol, 2,3-butylene glycol, etc.
  • the most preferable one is 1, 3-butylene glycol.
  • the formulating amount of said butylene glycol is not particularly restricted, but may for example be 30-60% (w/w), more preferably 40-50% (w/w) , most preferably 44-46% (w/w) .
  • diethylene glycol mono (lower ) alkyl ethers for use in this invention are diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, etc.
  • the most preferable one is diethylene glycol monoethyl ether.
  • the formulating amount of said diethylene glycol mono (lower) alkyl ethers is not particularly restricted, but may for example be 15-60% (w/w) , more preferably 20-50% (w/w), most preferably 25-45% (w/w) .
  • the thickeners which is usable in this invention is not particularly restricted provided that it is pharmaceutically acceptable and capable of imparting viscosity to the pharmaceutical base, thus including the following organic and inorganic water-soluble macromolecular substances, among others.
  • Organic substances - Native polymers gum Arabic, gum guar, carrageenan, gum tragacanth, pectin, starch, gumxanthan, gelatin, casein, dextrin, cellulose
  • Bentonite synthetic magnesium silicate, magnesium aluminosilicate, silicon dioxide, etc.
  • the amount of the thickener in the pharmaceutical composition can be judiciously selected according to the objective viscosity of the pharmaceutical composition.
  • the thickener is used in a proportion of preferably 0.1-10% (w/w), more preferably 0.5-5% (w/w) .
  • cellulose polymer such as hydroxypropylcellulose, carboxyvinyl polymer are more preferable, and the most preferable one is carboxyvinyl polymer. It is possible to change the touch of the pharmaceutical composition by changing them.
  • the pharmaceutical composition of this invention may contain the conventional excipient (e.g. lactose, sucrose, starch, mannitol, etc.), stabilizer [antioxidant (e.g. ascorbyl palmitate, tocopherol, etc.)], coloring agent, sweetener, perfume, diluent and preservative, as well as other medicinally active substances.
  • excipient e.g. lactose, sucrose, starch, mannitol, etc.
  • antioxidant e.g. ascorbyl palmitate, tocopherol, etc.
  • coloring agent e.g. ascorbyl palmitate, tocopherol, etc.
  • the pharmaceutical composition of this invention can be used by applying it to the affected site, particularly the skin lesion, once to 4 times daily.
  • the proper amount of said tricyclic compounds in the pharmaceutical composition is dependent on its particular species used, the patient's age, the type of disease and its severity, and other factors .
  • the recommended amount relative to the total composition is 0.00001-20% (w/w) , more preferably 0.0001-10% (w/w) , most preferably 0.001-3% (w/w) .
  • the composition may further contain one or more other drugs that are indicated in diseases of the skin.
  • composition of this invention can be produced in the same manner as described in the following examples.
  • FK506 substance is admixed as, its monohydrate when preparing compositions containing it, though its amount is expressed as the weight of FK506 substance, not of its monohydrate .
  • Example 1 FK506 substance 0.3 %(w/wl Isopropyl myristate 5.0 %(w/w)
  • Carboxyvinyl polymer (CP980NF) 2.5 %(w/w)
  • FK506 Substance was dissolved with diethylene glycol monoethyl ether . And then 1, 3-buthylene glycol and propylene carbonate were added. After visual check on the complete dissolution of FK506 substance, the dispersion of carboxyvinyl polymer in the binary system of isopropyl myristate and diethyl sebacate was added to obtain the desired viscosity and to provide a gel preparation for external application .
  • Example 2 According to a similar manner to Example 1, the following pharmaceutical compositions 2, 3,4 ,5 and 6 were prepared .
  • the whole blood concentration of FK506 Substance was determined by subjecting the blood sample to the enzyme immunoassay using a peroxidase (the assay system described in, for example, Japanese Kokai Tokkyo Koho Hl-92659) .
  • AUC [0-24 hr] denotes the area under the 0 ⁇ 24hr blood concentration-time curve.
  • carboxybinyl polymer could make FK506 stable, when FK506 was dissolved in lower alkanediols, such as ethylene glycol, propylene glycol, butylene glycol, etc.
  • lower alkanediols such as ethylene glycol, propylene glycol, butylene glycol, etc.
  • a combination of hydroxypropyl cellulose and ascorbyl palmitate could also make FK506 stable, when FK506 was dissolved in lower alkanediols, such as ethylene glycol, propylene glycol, butylene glycol, etc.
  • the present application further provides (i) a new use of carboxybinyl polymer for stabilizing the tricyclic compound (1) which is dissolved in lower alkanediols and (ii) a new use of a combination of hydroxypropyl cellulose and ascorbyl palmitate for stabilizing the tricyclic compound (1) which is dissolved in lower alkanediols.
  • a pharmaceutical composition containing the tricyclic compound (I) or its pharmaceutically acceptable salt which is very satisfactory in stability, workability, user acceptance, irritation potential, less skin sensitization and/or dermal penetration efficiency.
  • a gel preparation for external application could be provided which insures an improved penetration of the tricyclic compound (I) or its pharmaceutically acceptable salt, through the keratoid layer, which is a barrier to absorption, as well as a good cutaneous retention (particularly in the dermis) of the tricyclic compound.
  • the pharmaceutical composition of this invention has an adequate emollient (humectant) action and is free from the risk for dermatrophy and the so-called rebound phenomenon.
  • the pharmaceutical composition of the present invention is useful for the treatment or prevention of inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases (e.g. psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides , erythema, dermal eosinophilia, lupus erythematosus , acne, andalopecia areata) because of the pharmacologic activities possessed by the tricyclic compound.
  • immunologically-mediated diseases e.g. psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus
  • the gel preparatrion for external use of the present invention is useful for the treatment or prophylaxis of psoriasis, such as psoriasis arthropathica, psoriasis circinata, psoriasis diffusa, psoriasis discoidea, generalized pustular psoriasis of Zumbusch, psoriasis geographica, psoriasis guttata, psoriasis gyrata, psoriasis inveterata, psoriasis nummularis, psoriasis orbicularis, psoriasis ostreacea, psoriasis punctata, pustular psoriasis, psoriasis spondylitica, psoriasis universalis, and so on.
  • psoriasis such as psoriasis arthropathica,
  • composition of the present invention is also useful for the therapy or prophylaxis of the following diseases.
  • Autoimmune diseases of the eye e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet ' s disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye phlyctenule ⁇ iridocyclitis ⁇ sarcoidosis, endocrine ophthalmopathy, etc.); skin diseases (e.g. dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity, and cutaneous T-cell lymphoma) ; hypertrophic cicatrix or keloid due
  • transplantation of organs or tissues such as the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast ⁇ cartilage ⁇ etc.; graft-versus-host reactions following bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc.; infections caused by pathogenic microorganisms (e.g. Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.);
  • pathogenic microorganisms e.g. Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.
  • reversible obstructive airways diseases [asthma (e. g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness) bronchitis, etc.] ; mucosal or vascular inflammations (e.g. gastric ulcer, ischemic or thrombotic vascular injury, ischemicbowel diseases, enteritis, necrotizing enterocolitis, intestinal damages associated with thermal burns, leukotriene B4-mediated diseases); intestinal inflammations / allergies (e.g.
  • coeliac diseases proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn ' s disease and ulcerative colitis
  • food-related allergic diseases with symptomatic manifestation remote from the gastrointestinal tract (e.g. migrain, rhinitis and eczema)
  • renal diseases e.g. intestitial nephritis, Goodpasture ' s syndrome, hemolytic uremic syndrome, and diabetic nephropathy
  • nervous diseases e.g.
  • cerebral ischemic disease e.g., head injury, hemorrhage in brain (e.g., subarachnoid hemorrhage, intracerebral hemorrhage) , cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (TIA) , hypertensive encephalopathy, cerebral infarction
  • endocrine diseases e.g.
  • hyperthyroidism hyperthyroidism, and Basedow's disease
  • hematic diseases e.g. pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, and anerythroplasia
  • bone diseases e.g. osteoporosis
  • respiratory diseases e.g. sarcoidosis, pulmonary fibrosis, and idiopathic interstitial pneumonia
  • skin diseases e.g.
  • dermatomyositis leukoderma vulgaris, ichthyosis vulgaris, photosensitivity, and cutaneous T-cell lymphoma
  • circulatory diseases e.g. arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, and myocardosis
  • collagen diseases e.g. scleroderma, Wegener ' s granuloma, and
  • Sjogren's syndrome adiposis; eosinophilic fasciitis; periodontal diseases (e.g. damage to gingiva, periodontium, alveolar bone or substantia ossea dentis) ; nephrotic syndrome (e.g. glomerulonephritis) ; male pattern alopecia, alopecia senile; muscular dystrophy; pyoderma and Sezary syndrome; chromosome abnormality-associated diseases (e.g. Down's syndrome) ;
  • active oxygen-mediated diseases e.g. organ injury (e.g. ischemic circulation disorders of organs (e.g. heart, liver, kidney, digestive tract, etc.) associated with preservation, transplantation, or ischemic diseases (e.g. thrombosis, cardial infarction, etc. ) ) : intestinal diseases (e.g. endotoxin shock, pseudomembranous colitis, and drug- or radiation-induced colitis) : renal diseases (e.g. ischemic acute renal insufficiency, chronic renal failure) : pulmonary diseases (e.g. toxicosis caused by pulmonary oxygen or drugs (e.g.
  • organ injury e.g. ischemic circulation disorders of organs (e.g. heart, liver, kidney, digestive tract, etc.) associated with preservation, transplantation, or ischemic diseases (e.g. thrombosis, cardial infarction, etc. )
  • intestinal diseases e.g. endotoxin shock, pseudomembranous colitis, and drug
  • ocular diseases e.g. cataracta, iron-storage disease (siderosis bulbi), retinitis, pigmentosa, senile plaques, vitreous scarring, corneal alkali burn
  • dermatitis e.g. erythema multiforme, linear immunoglobulin A bullous dermatitis, cement dermatitis
  • other diseases e.g. gingivitis, periodontitis, sepsis, pancreatitis, and diseases causedby environmental pollution (e.g.
  • autoimmune diseases and inflammatory conditions e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e . g. arthritis deformans) , or polychondritis) ;
  • HIV Human Immunodeficiency Virus
  • the said tricyclic compound (I) has liver regenerating activity and/or activities of stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, the pharmaceutical composition of the present invention is useful for increasing the effect of the therapy and/or prophylaxis of liver diseases [e.g. immunogenic diseases (e.g. chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis or sclerosing cholangitis) , partial liver resection, acute liver necrosis (e.g.
  • immunogenic diseases e.g. chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis or sclerosing cholangitis
  • partial liver resection e.g.
  • hepatitis B necrosis caused by toxins, viral hepatitis, shock, or anoxia
  • hepatitis B e.g. fulminant hepatitis, late-onset hepatitis and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases)
  • hepatitis such as chronic hepatitis C
  • it is preferable to treat or prevent hepatitis, such as chronic hepatitis C by applying the tricyclic compounds (I) together with various interferons .
  • the present composition is also useful for increasing the effect of the prevention and/or treatment of various diseases because of the useful pharmacological activity of the said tricyclic compounds (I) , such as augmenting activity of chemotherapeutic effect, activity of cytomegalovirus infection, anti-inflammatory activity, inhibiting activity against peptidyl-prolyl isomerase or rota ase, antimalarial activity, antitumor activity, and so on.
  • useful pharmacological activity of the said tricyclic compounds (I) such as augmenting activity of chemotherapeutic effect, activity of cytomegalovirus infection, anti-inflammatory activity, inhibiting activity against peptidyl-prolyl isomerase or rota ase, antimalarial activity, antitumor activity, and so on.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un composé tricyclique (I) ou son sel pharmaceutiquement acceptable ; des esters d'acides gras d'alcool monohydrique, des diesters de diacides ; des carbonates d'alkylène inférieur ; du butylène glycol ; des éthers de mono alkyle (inférieur) de diéthylène glycol ; et des épaississants. Cette composition est satisfaisante du point de vue de ses caractéristiques de stabilité et de cinétique d'absorption et/ou pour son faible pouvoir irritant.
PCT/JP2002/005030 2001-05-28 2002-05-23 Composition pharmaceutique comprenant un compose tricyclique utile pour prevenir ou traiter les dermatoses WO2002096419A1 (fr)

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CA002448248A CA2448248A1 (fr) 2001-05-28 2002-05-23 Composition pharmaceutique comprenant un compose tricyclique utile pour prevenir ou traiter les dermatoses
US10/478,635 US20040220204A1 (en) 2001-05-28 2002-05-23 Pharmaceutical composition comprising a tricyclic compound for the prevention or treatment of skin diseases
JP2002592929A JP2005500269A (ja) 2001-05-28 2002-05-23 トリシクロ化合物を含有する皮膚疾患の予防または治療のための医薬組成物
BR0210251-0A BR0210251A (pt) 2001-05-28 2002-05-23 Composição farmacêutica contendo composto tricìclico e seu uso
IL15890002A IL158900A0 (en) 2001-05-28 2002-05-23 Pharmaceutical compositions containing a tricyclic compound for the prevention or treatment of skin diseases
EP02730703A EP1392297A1 (fr) 2001-05-28 2002-05-23 Composition pharmaceutique comprenant un compose tricyclique utile pour prevenir ou traiter les dermatoses
MXPA03010760A MXPA03010760A (es) 2001-05-28 2002-05-23 Composicion farmaceutica que comprende un compuesto triciclico para la prevencion o tratamiento de enfermedades de la piel.
PL02367634A PL367634A1 (en) 2001-05-28 2002-05-23 Pharmaceutical composition comprising a tricyclic compound for the prevention or treatment of skin diseases
HU0400020A HUP0400020A2 (hu) 2001-05-28 2002-05-23 Bőrbetegségek megelőzésére vagy kezelésére használható triciklusos vegyületet tartalmazó gyógyszerkészítmény
KR10-2003-7015071A KR20040002980A (ko) 2001-05-28 2002-05-23 트리사이클릭 화합물을 포함하는 피부 질환의 예방 또는치료용 약제학적 조성물
NO20035230A NO20035230D0 (no) 2001-05-28 2003-11-25 Farmasöytisk materiale omfattende en trisyklisk forbindelse for å hindre eller behandle hudsykdommer

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CN1537003A (zh) 2004-10-13
NO20035230D0 (no) 2003-11-25
EP1392297A1 (fr) 2004-03-03
BR0210251A (pt) 2004-08-10
JP2005500269A (ja) 2005-01-06
AUPR529701A0 (en) 2001-06-21
CZ20033251A3 (en) 2004-04-14

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